Drug delivery using intravascular injection of targeted nanocarriers (NCs) is a potent application of nanotechnology to treat disease. Many aspects of targeted drug nanocarrier design and medical use such as optimization of carrier size, concentration, surface coverage with targeting molecule and drug cargo packaging are amenable to multiscale computational modeling. Simulation used to provide predictive values of appropriate characteristics for manufacture and clinical application can reduce the time, expense and other resources necessary for otherwise large scale experimentation. For instance, hydrodynamic and microscopic interactions mediating NC motion and cargo offloading occurring in bloodflow, endothelial cell binding and cell internalization are complex interplay of defineable mechanical and molecular events occuring at multiple length and time scales. We hypothesize that computational modeling and simulation of these critical hydrodynamic and molecular events can be accessed to optimize design parameters such that nanocarriers loaded with trackable cargoes and decorated with targeting molecules to endothelial determinants (e.g., ICAM-1 surface molecules) will: i) efficiently bid to endothelial cells, ii) enter endothelial endosomes and, iii) effectively unload their cargo in this compartment. We propose to develop and validate a multiscale computational modeling platform to optimize endothelial drug delivery, including dispersal of the delivered cargo within target cells. Our model includes sensitivity analysis~ it will be validated through synergistic animal and cell culture experiments of NC binding mechanics and intracellular cargo offloading efficiency. This will be accomplished via three specific aims: Aim 1: Multiscal modeling of hydrodynamic and microscopic interactions mediating NC motion in vascular targeted drug delivery involving three distinct scales: a macroscopic regime, a lubrication regime and an adhesion regime. Aim 2: Multiscale modeling of transport and controlled drug release from a targeted NC in blood flow. The computational model approaches in Aims 1 and 2 will be tuned using sensitivity analysis on important governing parameters. Aim 3: Experimentally quantify NC targeting kinetics (using prototype anti-ICAM and alternative surface molecules), carrier internalization and intracellular drug delivery using dextran hydrogel nanocarriers loaded with prototype model fluorescence-labeled cargoes. We will utilize physiologically relevant in vitro and in vivo systems forthese experiments. Validation of numerical simulation results (Aims 1 and 2) will be made by comparison of predictions with experimentally observed transport and release properties (Aim 3). Our team of Engineers, Materials Scientists, Pharmacologists and Vascular Biologists brings combined expertise in modeling and experimental approaches that are versatile. This will enable us to adapt protocols to specific applications for optimal engineering design and clinical translation of NC drug delivery for targeted disease treatment.